Gastric cancer has a high mortality rate associated with its late stage diagnosis. Although Gp130 knock-in mutant mice (gp130^F/F) develop benign gastric tumours dependent upon IL-11-induced Stat3/mTORC activation with hallmarks of early stage intestinal-type gastric cancer in humans [1, 2], there is an urgent need to develop mouse models that mimic the progression from adenoma to carcinoma and metastasis. Macrophages are a major component of the tumour micro-environment, and their increased numbers and alternative activation is commonly associated with tumour progression and metastasis.

Haematopoietic Cell Kinase (Hck) is a myeloid-specific Src family kinase that is involved in polarization of alternatively activated macrophages, which correlate with a poor prognosis for human gastric cancer. To establish whether aberrant Hck activation would induce tumourigenesis, Hck mutant mice that exhibit constitutive kinase activation (Hck^Up/Up) were crossed with gp130^F/+ mice that are predisposed to gastric tumour development. Surprisingly, the resulting gp130^F/+;Hck^Up/Up compound mutants developed tumours similar to gp130^F/F animals, while gp130^F/+ mice remained tumour-free. Furthermore, tumours in 9 month old gp130^F/+;Hck^Up/Up mutants showed sub-mucosal invasion, which was not observed in gp130^F/F mice.

Western blotting and immunohistochemical analysis revealed a significant increase in tumour cell proliferation in gp130^F/+;Hck^Up/Up mutants compared to gp130^F/F animals, consistent with an increased abundance of the activated forms of Stat3, Erk, Akt and S6 cytoplasmic signalling proteins. While the total number of macrophages remained unaffected, qPCR analysis of purified tumour-associated macrophages from gp130^F/+;Hck^Up/Up mice showed a significant increase in markers of alternative macrophage activation, including Il4, Il13, Arg1 and Ym1 when compared to cells from gp130^F/F animals. Furthermore, reciprocal adoptive transfer of Hck^Up/Up bone-marrow into gp130 mutant recipients was sufficient to increase tumour burden and promote alternative macrophage polarisation.

Collectively, our results demonstrate that aberrant Hck activation promotes polarisation towards alternative macrophage activation and confers an invasive gastric cancer phenotype.